Delivery of sumatriptan, frovatriptan or naratriptan through an inhalation route

ABSTRACT

The present invention relates to the delivery of anti-migraine compounds through an inhalation route. Specifically, it relates to aerosols containing sumatriptan, frovatriptan, or naratriptan that are used in inhalation therapy. In a composition aspect of the present invention, the aerosol comprises particles comprising at least 5 percent by weight of sumatriptan, frovatriptan, or naratriptan. In a method aspect of the present invention, one of sumatriptan, frovatriptan, or naratriptan is delivered to a mammal through an inhalation route. The method comprises: a) heating a composition, wherein the composition comprises at least 5 percent by weight of sumatriptan, frovatriptan, or naratriptan, to form a vapor; and, b) allowing the vapor to cool, thereby forming a condensation aerosol comprising particles, which is inhaled by the mammal. In a kit aspect of the present invention, a kit for delivering sumatriptan, frovatriptan, or naratriptan through an inhalation route to a mammal is provided which comprises: a) a composition comprising at least 5 percent by weight of sumatriptan, frovatriptan, or naratriptan; and, b) a device that forms a sumatriptan, frovatriptan, or naratriptan aerosol from the composition, for inhalation by the mammal.

This application claims priority to U.S. provisional application Ser.No. 60/294,203 entitled “Thermal Vapor Delivery of Drugs,” filed May 24,2001, Rabinowitz and Zaffaroni, the entire disclosure of which is herebyincorporated by reference. This application further claims priority toU.S. provisional application Ser. No. 60/317,479 entitled “Aerosol DrugDelivery,” filed Sep. 5, 2001, Rabinowitz and Zaffaroni, the entiredisclosure of which is hereby incorporated by reference.

FIELD OF THE INVENTION

The present invention relates to the delivery of anti-migraine compoundsthrough an inhalation route. Specifically, it relates to aerosolscontaining sumatriptan, frovatriptan, or naratriptan that are used ininhalation therapy.

BACKGROUND OF THE INVENTION

There are a number of compositions currently marketed for the treatmentof migraine headaches. The compositions contain at least one activeingredient that provides for observed therapeutic effects. Among theactive ingredients given in such anti-migraine compositions aresumatriptan, frovatriptan, and naratriptan.

It is desirable to provide a new route of administration forsumatriptan, frovatriptan, and naratriptan that rapidly produces peakplasma concentrations of the compounds. The provision of such a route isan object of the present invention.

SUMMARY OF THE INVENTION

The present invention relates to the delivery of anti-migraine compoundsthrough an inhalation route. Specifically, it relates to aerosolscontaining sumatriptan, frovatriptan, or naratriptan that are used ininhalation therapy.

In a composition aspect of the present invention, the aerosol comprisesparticles comprising at least 5 percent by weight of sumatriptan,frovatriptan, or naratriptan. Preferably, the particles comprise atleast 10 percent by weight of sumatriptan, frovatriptan, or naratriptan.More preferably, the particles comprise at least 20 percent, 30 percent,40 percent, 50 percent, 60 percent, 70 percent, 80 percent, 90 percent,95 percent, 97 percent, 99 percent, 99.5 percent or 99.97 percent byweight of sumatriptan, frovatriptan, or naratriptan.

Typically, the aerosol has a mass of at least 10 μg. Preferably, theaerosol has a mass of at least 100 μg. More preferably, the aerosol hasa mass of at least 200 μg.

Typically, the particles comprise less than 10 percent by weight ofsumatriptan, frovatriptan, or naratriptan degradation products.Preferably, the particles comprise less than 5 percent by weight ofsumatriptan, frovatriptan, or naratriptan degradation products. Morepreferably, the particles comprise less than 2.5, 1, 0.5, 0.1 or 0.03percent by weight of sumatriptan, frovatriptan, or naratriptan.

Typically, the particles comprise less than 90 percent by weight ofwater. Preferably, the particles comprise less than 80 percent by weightof water. More preferably, the particles comprise less than 70 percent,60 percent, 50 percent, 40 percent, 30 percent, 20 percent, 10 percent,or 5 percent by weight of water.

Typically, at least 50 percent by weight of the aerosol is amorphous inform, wherein crystalline forms make up less than 50 percent by weightof the total aerosol weight, regardless of the nature of individualparticles. Preferably, at least 75 percent by weight of the aerosol isamorphous in form. More preferably, at least 90 percent by weight of theaerosol is amorphous in form.

Typically, where the aerosol comprises sumatriptan, the aerosol has aninhalable aerosol drug mass density of between 5 mg/L and 40 mg/L.Preferably, the aerosol has an inhalable aerosol drug mass density ofbetween 10 mg/L and 35 mg/L. More preferably, the aerosol has aninhalable aerosol drug mass density of between 15 mg/L and 30 mg/L.

Typically, where the aerosol comprises frovatriptan, the aerosol has aninhalable aerosol drug mass density of between 0.5 mg/L and 4 mg/L.Preferably, the aerosol has an inhalable aerosol drug mass density ofbetween 1 mg/L and 3.5 mg/L. More preferably, the aerosol has aninhalable aerosol drug mass density of between 1.5 mg/L and 3.0 mg/L.

Typically, where the aerosol comprises naratriptan, the aerosol has aninhalable aerosol drug mass density of between 0.2 mg/L and 2 mg/L.Preferably, the aerosol has an inhalable aerosol drug mass density ofbetween 0.3 mg/L and 1.75 mg/L. More preferably, the aerosol has aninhalable aerosol drug mass density of between 0.4 mg/L and 1.5 mg/L.

Typically, the aerosol has an inhalable aerosol particle density greaterthan 10⁶ particles/mL. Preferably, the aerosol has an inhalable aerosolparticle density greater than 10⁷ particles/mL or 10⁸ particles/mL.

Typically, the aerosol particles have a mass median aerodynamic diameterof less than 5 microns. Preferably, the particles have a mass medianaerodynamic diameter of less than 3 microns. More preferably, theparticles have a mass median aerodynamic diameter of less than 2 or 1micron(s).

Typically, the geometric standard deviation around the mass medianaerodynamic diameter of the aerosol particles is less than 3.0.Preferably, the geometric standard deviation is less than 2.5. Morepreferably, the geometric standard deviation is less than 2.2.

Typically, the aerosol is formed by heating a composition containingsumatriptan, frovatriptan, or naratriptan to form a vapor andsubsequently allowing the vapor to condense into an aerosol.

In another composition aspect of the present invention, a dose form ofan antimigraine compound is provided for the treatment of migraine,wherein the dose form comprises less than the typical oral dose of theantimigraine compound.

Typically, where the antimigraine compound is sumitriptan, the dose formcomprises less than 20 mg of sumitriptan. Preferably, the dose formcomprises less than 15 mg of sumitriptan. More preferably, the dose formcomprises less than 10 mg or 5 mg of sumitriptan.

Typically, where the antimigraine compound is frovatriptan, the doseform comprises less than 2 mg of frovatriptan. Preferably, the dose formcomprises less than 1.75 mg of frovatriptan. More preferably, the doseform comprises less than 1.5 mg, 1.25 mg or 1 mg of frovatriptan.

Typically, where the antimigraine compound is naratriptan, the dose formcomprises less than 0.8 mg of naratriptan. Preferably, the dose formcomprises less than 0.6 mg of naratriptan. More preferably, the dose forcomprises less than 0.4 mg of naratriptan.

Typically, the dose form further comprises less than 90 percent byweight of water. Preferably, the dose form further comprises less than80 percent by weight of water. More preferably, the dose form furthercomprises less than 70 percent, 60 percent, 50 percent, 40 percent, 30percent, 20 percent, or 10 percent by weight of water.

Typically, the dose form further comprises less than 90 percent byweight of a pharmaceutically acceptable excipient. Preferably, the doseform further comprises less than 80 percent by weight of apharmaceutically acceptable excipient. More preferably, the dose formfurther comprises less than 70 percent, 60 percent, 50 percent, 40percent, 30 percent, 20 percent, or 10 percent by weight of apharmaceutically acceptable excipient.

In a method aspect of the present invention, one of sumatriptan,frovatriptan, or naratriptan is delivered to a mammal through aninhalation route. The method comprises: a) heating a composition,wherein the composition comprises at least 5 percent by weight ofsumatriptan, frovatriptan, or naratriptan, to form a vapor; and, b)allowing the vapor to cool, thereby forming a condensation aerosolcomprising particles, which is inhaled by the mammal. Preferably, thecomposition that is heated comprises at least 10 percent by weight ofsumatriptan, frovatriptan, or naratriptan. More preferably, thecomposition comprises at least 20 percent, 30 percent, 40 percent, 50percent, 60 percent, 70 percent, 80 percent, 90 percent, 95 percent, 97percent, 99 percent, 99.5 percent, 99.9 percent or 99.97 percent byweight of sumatriptan, frovatriptan, or naratriptan.

Typically, the particles comprise at least 5 percent by weight ofsumatriptan, frovatriptan, or naratriptan. Preferably, the particlescomprise at least 10 percent by weight of sumatriptan, frovatriptan, ornaratriptan. More preferably, the particles comprise at least 20percent, 30 percent, 40 percent, 50 percent, 60 percent, 70 percent, 80percent, 90 percent, 95 percent, 97 percent, 99 percent, 99.5 percent,99.9 percent or 99.97 percent by weight of sumatriptan, frovatriptan, ornaratriptan.

Typically, the aerosol has a mass of at least 10 μg. Preferably, theaerosol has a mass of at least 100 μg. More preferably, the aerosol hasa mass of at least 200 μg.

Typically, the particles comprise less than 10 percent by weight ofsumatriptan, frovatriptan, or naratriptan degradation products.Preferably, the particles comprise less than 5 percent by weight ofsumatriptan, frovatriptan, or naratriptan degradation products. Morepreferably, the particles comprise 2.5, 1, 0.5, 0.1 or 0.03 percent byweight of sumatriptan, frovatriptan, or naratriptan degradationproducts.

Typically, the particles comprise less than 90 percent by weight ofwater. Preferably, the particles comprise less than 80 percent by weightof water. More preferably, the particles comprise less than 70 percent,60 percent, 50 percent, 40 percent, 30 percent, 20 percent, 10 percent,or 5 percent by weight of water.

Typically, at least 50 percent by weight of the aerosol is amorphous inform, wherein crystalline forms make up less than 50 percent by weightof the total aerosol weight, regardless of the nature of individualparticles. Preferably, at least 75 percent by weight of the aerosol isamorphous in form. More preferably, at least 90 percent by weight of theaerosol is amorphous in form.

Typically, the particles of the delivered condensation aerosol have amass median aerodynamic diameter of less than 5 microns. Preferably, theparticles have a mass median aerodynamic diameter of less than 3microns. More preferably, the particles have a mass median aerodynamicdiameter of less than 2 or 1 micron(s).

Typically, the geometric standard deviation around the mass medianaerodynamic diameter of the aerosol particles is less than 3.0.Preferably, the geometric standard deviation is less than 2.5. Morepreferably, the geometric standard deviation is less than 2.2.

Typically, where the aerosol comprises sumatriptan, the deliveredaerosol has an inhalable aerosol drug mass density of between 5 mg/L and40 mg/L. Preferably, the aerosol has an inhalable aerosol drug massdensity of between 10 mg/L and 35 mg/L. More preferably, the aerosol hasan inhalable aerosol drug mass density of between 15 mg/L and 30 mg/L.

Typically, where the aerosol comprises frovatriptan, the deliveredaerosol has an inhalable aerosol drug mass density of between 0.5 mg/Land 4 mg/L. Preferably, the aerosol has an inhalable aerosol drug massdensity of between 1 mg/L and 3.5 mg/L. More preferably, the aerosol hasan inhalable aerosol drug mass density of between 1.5 mg/L and 3.0 mg/L.

Typically, where the aerosol comprises naratriptan, the deliveredaerosol has an inhalable aerosol drug mass density of between 0.2 mg/Land 2 mg/L. Preferably, the aerosol has an inhalable aerosol drug massdensity of between 0.3 mg/L and 1.75 mg/L. More preferably, the aerosolhas an inhalable aerosol drug mass density of between 0.4 mg/L and 1.5mg/L.

Typically, the delivered aerosol has an inhalable aerosol particledensity greater than 10⁶ particles/mL. Preferably, the aerosol has aninhalable aerosol particle density greater than 10⁷ particles/mL or 10⁸particles/mL.

Typically, the rate of inhalable aerosol particle formation of thedelivered condensation aerosol is greater than 10⁸ particles per second.Preferably, the aerosol is formed at a rate greater than 10⁹ inhalableparticles per second. More preferably, the aerosol is formed at a rategreater than 10¹⁰ inhalable particles per second.

Typically, the delivered condensation aerosol is formed at a rategreater than 0.5 mg/second. Preferably, the aerosol is formed at a rategreater than 0.75 mg/second. More preferably, the aerosol is formed at arate greater than 1 mg/second, 1.5 mg/second or 2 mg/second.

Typically, where the condensation aerosol comprises sumatriptan, between5 mg and 40 mg of sumatriptan are delivered to the mammal in a singleinspiration. Preferably, between 10 mg and 35 mg of sumatriptan aredelivered to the mammal in a single inspiration. More preferably,between 15 mg and 30 mg of sumatriptan are delivered in a singleinspiration.

Typically, where the condensation aerosol comprises frovatriptan,between 0.5 mg and 4 mg of frovatriptan are delivered to the mammal in asingle inspiration. Preferably, between 1 mg and 3.5 mg of frovatriptanare delivered to the mammal in a single inspiration. More preferably,between 1.5 mg and 3.0 mg of frovatriptan are delivered in a singleinspiration.

Typically, where the condensation aerosol comprises naratriptan, between0.2 mg and 2 mg of naratriptan are delivered to the mammal in a singleinspiration. Preferably, between 0.3 mg and 1.75 mg of naratriptan aredelivered to the mammal in a single inspiration. More preferably,between 0.4 mg and 1.5 mg of naratriptan are delivered in a singleinspiration.

Typically, the delivered condensation aerosol results in a peak plasmaconcentration of sumatriptan, frovatriptan, or naratriptan in the mammalin less than 1 h. Preferably, the peak plasma concentration is reachedin less than 0.5 h. More preferably, the peak plasma concentration isreached in less than 0.2, 0.1, 0.05, 0.02, 0.01, or 0.005 h (arterialmeasurement).

Typically, where the condensation aerosol comprises sumatriptan, lessthan 20 mg of sumitriptan is inhaled by the mammal in any 2 hour period.Preferably, less than 15 mg of sumitriptan is inhaled by the mammal inany 2 hour period. More preferably, less than 10 mg or 5 mg ofsumitriptan is inhaled by the mammal in any 2 hour period.

Typically, where the condensation aerosol comprises frovatriptan, lessthan 2 mg of frovatriptan is inhaled by the mammal in any 2 hour period.Preferably, less than 1.75 mg of frovatriptan is inhaled by the mammalin any 2 hour period. More preferably, less than 1.5 mg of frovatriptanis inhaled by the mammal in any 2 hour period.

Typically, where the condensation aerosol comprises naratriptan, lessthan 0.8 mg of naratriptan is inhaled by the mammal in any 2 hourperiod. Preferably, less than 0.6 mg of naratriptan is inhaled by themammal in any 2 hour period. More preferably, less than 0.4 mg ofnaratriptan is inhaled by the mammal in any 2 hour period.

In another method aspect of the present invention, a method of treatingmigraine is provided which comprises administering a dose of anantimigraine compound to a mammal that is less than the typical oraldose.

Typically, where the antimigraine compound is sumatriptan, less than 20mg of sumitriptan is administered to the mammal in any 2 hour period.Preferably, less than 15 mg of sumitriptan is administered to the mammalin any 2 hour period. More preferably, less than 10 mg or 5 mg ofsumitriptan is administered to the mammal in any 2 hour period.

Typically, where the antimigraine compound is frovatriptan, less than 2mg of frovatriptan is administered to the mammal in any 2 hour period.Preferably, less than 1.75 mg of frovatriptan is administered to themammal in any 2 hour period. More preferably, less than 1.5 mg, 1.25 mg,or 1 mg of frovatriptan is administered to the mammal in any 2 hourperiod.

Typically, where the antimigraine compound is naratriptan, less than 0.8mg of naratriptan is administered to the mammal in any 2 hour period.Preferably, less than 0.6 mg of naratriptan is administered to themammal in any 2 hour period. More preferably, less than 0.4 mg ofnaratriptan is inhaled by the mammal in any 2 hour period.

In a kit aspect of the present invention, a kit for deliveringsumatriptan, frovatriptan, or naratriptan through an inhalation route toa mammal is provided which comprises: a) a composition comprising atleast 5 percent by weight of sumatriptan, frovatriptan, or naratriptan;and, b) a device that forms a sumatriptan, frovatriptan, or naratriptanaerosol from the composition, for inhalation by the mammal. Preferably,the composition comprises at least 20 percent, 30 percent, 40 percent,50 percent, 60 percent, 70 percent, 80 percent, 90 percent, 95 percent,97 percent, 99 percent, 99.5 percent, 99.9 percent or 99.97 percent byweight of sumatriptan, frovatriptan, or naratriptan.

Typically, the device contained in the kit comprises: a) an element forheating the sumatriptan, frovatriptan, or naratriptan composition toform a vapor; b) an element allowing the vapor to cool to form anaerosol; and, c) an element permitting the mammal to inhale the aerosol.

Typically, where the kit comprises sumitriptan, it comprises less than20 mg of sumitriptan. Preferably, the kit comprises less than 15 mg ofsumitriptan. More preferably, it comprises less than 10 mg or 5 mg ofsumitriptan.

Typically, where the kit comprises frovatriptan, it comprises less than2 mg of frovatriptan. Preferably, the kit comprises less than 1.75 mg offrovatriptan. More preferably, it comprises less than 1.5 mg, 1.25 mg,or 1 mg of frovatriptan.

Typically, where the kit comprises naratriptan, it comprises less than0.8 mg of naratriptan. Preferably, the kit comprises less than 0.6 mg ofnaratriptan. More preferably, the kit comprises less than 0.4 mg ofnaratriptan.

BRIEF DESCRIPTION OF THE FIGURE

FIG. 1 shows a cross-sectional view of a device used to deliversumatriptan, frovatriptan, or naratriptan aerosols to a mammal throughan inhalation route.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

“Aerodynamic diameter” of a given particle refers to the diameter of aspherical droplet with a density of 1 g/mL (the density of water) thathas the same settling velocity as the given particle.

“Aerosol” refers to a suspension of solid or liquid particles in a gas.

“Aerosol drug mass density” refers to the mass of sumatriptan,frovatriptan, or naratriptan per unit volume of aerosol.

“Aerosol mass density” refers to the mass of particulate matter per unitvolume of aerosol.

“Aerosol particle density” refers to the number of particles per unitvolume of aerosol.

“Amorphous particle” refers to a particle that does not contain morethan 50 percent by weight of a crystalline form. Preferably, theparticle does not contain more than 25 percent by weight of acrystalline form. More preferably, the particle does not contain morethan 10 percent by weight of a crystalline form.

“Condensation aerosol” refers to an aerosol formed by vaporization of asubstance followed by condensation of the substance into an aerosol.

“Frovatriptan” refers to3-methylamino-6-carboxamido-1,2,3,4-tetrahydrocarbazole.

“Frovatriptan degradation product” refers to a compound resulting from achemical modification of frovatriptan. The modification, for example,can be the result of a thermally or photochemically induced reaction.Such reactions include, without limitation, oxidation and hydrolysis.

“Inhalable aerosol drug mass density” refers to the aerosol drug massdensity produced by an inhalation device and delivered into a typicalpatient tidal volume.

“Inhalable aerosol mass density” refers to the aerosol mass densityproduced by an inhalation device and delivered into a typical patienttidal volume.

“Inhalable aerosol particle density” refers to the aerosol particledensity of particles of size between 100 nm and 5 microns produced by aninhalation device and delivered into a typical patient tidal volume.

“Naratriptan” refers toN-methyl-3-(1-methyl-4-piperidinyl)-1H-indole-5-ethane-sulfonamide.

“Naratriptan degradation product” refers to a compound resulting from achemical modification of naratriptan. The modification, for example, canbe the result of a thermally or photochemically induced reaction. Suchreactions include, without limitation, oxidation and hydrolysis.

“Mass median aerodynamic diameter” or “MMAD” of an aerosol refers to theaerodynamic diameter for which half the particulate mass of the aerosolis contributed by particles with an aerodynamic diameter larger than theMMAD and half by particles with an aerodynamic diameter smaller than theMMAD.

“Rate of aerosol formation” refers to the mass of aerosolizedparticulate matter produced by an inhalation device per unit time.

“Rate of inhalable aerosol particle formation” refers to the number ofparticles of size between 100 nm and 5 microns produced by an inhalationdevice per unit time.

“Rate of drug aerosol formation” refers to the mass of aerosolizedsumatriptan, frovatriptan, or naratriptan produced by an inhalationdevice per unit time.

“Settling velocity” refers to the terminal velocity of an aerosolparticle undergoing gravitational settling in air.

“Sumatriptan” refers to3-[2-(dimethylamino)ethyl]-N-methyl-1H-indole-5-methanesulfonamide.

“Sumatriptan degradation product” refers to a compound resulting from achemical modification of sumatriptan. The modification, for example, canbe the result of a thermally or photochemically induced reaction. Suchreactions include, without limitation, oxidation and hydrolysis.

“Typical patient tidal volume” refers to 1 L for an adult patient and 15mL/kg for a pediatric patient.

“Vapor” refers to a gas, and “vapor phase” refers to a gas phase. Theterm “thermal vapor” refers to a vapor phase, aerosol, or mixture ofaerosol-vapor phases, formed preferably by heating.

Formation of Sumatriptan, Frovatriptan, or Naratriptan ContainingAerosols

Any suitable method is used to form the aerosols of the presentinvention. A preferred method, however, involves heating a compositioncomprising sumatriptan, frovatriptan, or naratriptan to form a vapor,followed by cooling of the vapor such that it condenses to provide asumatriptan, frovatriptan, or naratriptan comprising aerosol(condensation aerosol). The composition is heated in one of four forms:as pure active compound (i.e., pure sumatriptan, frovatriptan, ornaratriptan); as a mixture of active compound and a pharmaceuticallyacceptable excipient; as a salt form of the pure active compound; and,as a mixture of active compound salt form and a pharmaceuticallyacceptable excipient.

Salt forms of sumatriptan, frovatriptan, or naratriptan are eithercommercially available or are obtained from the corresponding free baseusing well known methods in the art. A variety of pharmaceuticallyacceptable salts are suitable for aerosolization. Such salts include,without limitation, the following: hydrochloric acid, hydrobromic acid,acetic acid, maleic acid, formic acid, and fumaric acid salts.

Pharmaceutically acceptable excipients may be volatile or nonvolatile.Volatile excipients, when heated, are concurrently volatilized,aerosolized and inhaled with sumatriptan, frovatriptan, or naratriptan.Classes of such excipients are known in the art and include, withoutlimitation, gaseous, supercritical fluid, liquid and solid solvents. Thefollowing is a list of exemplary carriers within the classes: water;terpenes, such as menthol; alcohols, such as ethanol, propylene glycol,glycerol and other similar alcohols; dimethylformamide;dimethylacetamide; wax; supercritical carbon dioxide; dry ice; andmixtures thereof.

Solid supports on which the composition is heated are of a variety ofshapes. Examples of such shapes include, without limitation, cylindersof less than 1.0 mm in diameter, boxes of less than 1.0 mm thickness andvirtually any shape permeated by small (e.g., less than 1.0 mm-sized)pores. Preferably, solid supports provide a large surface to volumeratio (e.g., greater than 100 per meter) and a large surface to massratio (e.g., greater than 1 cm² per gram).

A solid support of one shape can also be transformed into another shapewith different properties. For example, a flat sheet of 0.25 mmthickness has a surface to volume ratio of approximately 8,000 permeter. Rolling the sheet into a hollow cylinder of 1 cm diameterproduces a support that retains the high surface to mass ratio of theoriginal sheet but has a lower surface to volume ratio (about 400 permeter).

A number of different materials are used to construct the solidsupports. Classes of such materials include, without limitation, metals,inorganic materials, carbonaceous materials and polymers. The followingare examples of the material classes: aluminum, silver, gold, stainlesssteel, copper and tungsten; silica, glass, silicon and alumina;graphite, porous carbons, carbon yams and carbon felts;polytetrafluoroethylene and polyethylene glycol. Combinations ofmaterials and coated variants of materials are used as well.

Where aluminum is used as a solid support, aluminum foil is a suitablematerial. Examples of silica, alumina and silicon based materialsinclude amphorous silica S-5631 (Sigma, St. Louis, Mo.), BCR171 (analumina of defined surface area greater than 2 m²/g from Aldrich, St.Louis, Mo.) and a silicon wafer as used in the semiconductor industry.Carbon yams and felts are available from American Kynol, Inc., New York,N.Y. Chromatography resins such as octadecycl silane chemically bondedto porous silica are exemplary coated variants of silica.

The heating of the sumatriptan, frovatriptan, or naratriptancompositions is performed using any suitable method. Examples of methodsby which heat can be generated include the following: passage of currentthrough an electrical resistance element; absorption of electromagneticradiation, such as microwave or laser light; and, exothermic chemicalreactions, such as exothermic solvation, hydration of pyrophoricmaterials and oxidation of combustible materials.

Delivery of Sumatriptan, Frovatriptan, or Naratriptan ContainingAerosols

Sumatriptan, frovatriptan, or naratriptan containing aerosols of thepresent invention are delivered to a mammal using an inhalation device.Where the aerosol is a sumatriptan, frovatriptan, or naratriptancontaining composition to form a vapor; an element allowing the vapor tocool, thereby providing a condensation aerosol; and, an elementpermitting the mammal to inhale the aerosol. Various suitable heatingmethods are described above. The element that allows cooling is, in itsimplest form, an inert passageway linking the heating means to theinhalation means. The element permitting inhalation is an aerosol exitportal that forms a connection between the cooling element and themammal's respiratory system.

One device used to deliver the sumatriptan, frovatriptan, or naratriptancontaining aerosol is described in reference to FIG. 1. Delivery device100 has a proximal end 102 and a distal end 104, a heating module 106, apower source 108, and a mouthpiece 110. A sumatriptan, frovatriptan, ornaratriptan composition is deposited on a surface 112 of heating module106. Upon activation of a user activated switch 114, power source 108initiates heating of heating module 106 (e.g, through ignition ofcombustible fuel or passage of current through a resistive heatingelement). The sumatriptan, frovatriptan, or naratriptan compositionvolatilizes due to the heating of heating module 106 and condenses toform a condensation aerosol prior to reaching the mouthpiece 110 at theproximal end of the device 102. Air flow traveling from the devicedistal end 104 to the mouthpiece 110 carries the condensation aerosol tothe mouthpiece 110, where it is inhaled by the mammal.

Devices, if desired, contain a variety of components to facilitate thedelivery of sumatriptan, frovatriptan, or naratriptan containingaerosols. For instance, the device may include any component known inthe art to control the timing of drug aerosolization relative toinhalation (e.g., breath-actuation), to provide feedback to patients onthe rate and/or volume of inhalation, to prevent excessive use (i.e.,“lock-out” feature), to prevent use by unauthorized individuals, and/orto record dosing histories.

Dosage of Sumatriptan, Frovatriptan, or Naratriptan Containing Aerosols

Sumatriptan, frovatriptan, and naratriptan are given at strengths of 25mg, 2.5 mg, and 1 mg respectively for the treatment of migraineheadaches. As aerosols, 5 mg to 40 mg of sumatriptan, 0.5 mg to 4 mg offrovatriptan, and 0.2 mg to 2 mg naratriptan are generally provided forthe same indication. A typical dosage of a sumatriptan, frovatriptan, ornaratriptan aerosol is either administered as a single inhalation or asa series of inhalations taken within an hour or less (dosage equals sumof inhaled amounts). Where the drug is administered as a series ofinhalations, a different amount may be delivered in each inhalation. Thedosage amount of sumatriptan, frovatriptan, or naratriptan in aerosolform is generally no greater than twice the standard dose of the druggiven orally.

One can determine the appropriate dose of sumatriptan, frovatriptan, ornaratriptan containing aerosols to treat a particular condition usingmethods such as animal experiments and a dose-finding (Phase I/II)clinical trial. One animal experiment involves measuring plasmaconcentrations of drug in an animal after its exposure to the aerosol.Mammals such as dogs or primates are typically used in such studies,since their respiratory systems are similar to that of a human. Initialdose levels for testing in humans is generally less than or equal to thedose in the mammal model that resulted in plasma drug levels associatedwith a therapeutic effect in humans. Dose escalation in humans is thenperformed, until either an optimal therapeutic response is obtained or adose-limiting toxicity is encountered.

Analysis of Sumatriptan, Frovatriptan, or Naratriptan ContainingAerosols

Purity of a sumatriptan, frovatriptan, or naratriptan containing aerosolis determined using a number of methods, examples of which are describedin Sekine et al., Journal of Forensic Science 32:1271-1280 (1987) andMartin et al., Journal of Analytic Toxicology 13:158-162 (1989). Onemethod involves forming the aerosol in a device through which a gas flow(e.g., air flow) is maintained, generally at a rate between 0.4 and 60L/min. The gas flow carries the aerosol into one or more traps. Afterisolation from the trap, the aerosol is subjected to an analyticaltechnique, such as gas or liquid chromatography, that permits adetermination of composition purity.

A variety of different traps are used for aerosol collection. Thefollowing list contains examples of such traps: filters; glass wool;impingers; solvent traps, such as dry ice-cooled ethanol, methanol,acetone and dichloromethane traps at various pH values; syringes thatsample the aerosol; empty, low-pressure (e.g., vacuum) containers intowhich the aerosol is drawn; and, empty containers that fully surroundand enclose the aerosol generating device. Where a solid such as glasswool is used, it is typically extracted with a solvent such as ethanol.The solvent extract is subjected to analysis rather than the solid(i.e., glass wool) itself. Where a syringe or container is used, thecontainer is similarly extracted with a solvent.

The gas or liquid chromatograph discussed above contains a detectionsystem (i.e., detector). Such detection systems are well known in theart and include, for example, flame ionization, photon absorption andmass spectrometry detectors. An advantage of a mass spectrometrydetector is that it can be used to determine the structure ofsumatriptan, frovatriptan, or naratriptan degradation products.

Particle size distribution of a sumatriptan, frovatriptan, ornaratriptan containing aerosol is determined using any suitable methodin the art (e.g., cascade impaction). An Andersen Eight Stage Non-viableCascade Impactor (Andersen Instruments, Smyrna, Ga.) linked to a furnacetube by a mock throat (USP throat, Andersen Instruments, Smyrna, Ga.) isone system used for cascade impaction studies.

Inhalable aerosol mass density is determined, for example, by deliveringa drug-containing aerosol into a confined chamber via an inhalationdevice and measuring the mass collected in the chamber. Typically, theaerosol is drawn into the chamber by having a pressure gradient betweenthe device and the chamber, wherein the chamber is at lower pressurethan the device. The volume of the chamber should approximate the tidalvolume of an inhaling patient.

Inhalable aerosol drug mass density is determined, for example, bydelivering a drug-containing aerosol into a confined chamber via aninhalation device and measuring the amount of active drug compoundcollected in the chamber. Typically, the aerosol is drawn into thechamber by having a pressure gradient between the device and thechamber, wherein the chamber is at lower pressure than the device. Thevolume of the chamber should approximate the tidal volume of an inhalingpatient. The amount of active drug compound collected in the chamber isdetermined by extracting the chamber, conducting chromatographicanalysis of the extract and comparing the results of the chromatographicanalysis to those of a standard containing known amounts of drug.

Inhalable aerosol particle density is determined, for example, bydelivering aerosol phase drug into a confined chamber via an inhalationdevice and measuring the number of particles of given size collected inthe chamber. The number of particles of a given size may be directlymeasured based on the light-scattering properties of the particles.Alternatively, the number of particles of a given size is determined bymeasuring the mass of particles within the given size range andcalculating the number of particles based on the mass as follows: Totalnumber of particles=Sum (from size range 1 to size range N) of number ofparticles in each size range. Number of particles in a given sizerange=Mass in the size range/Mass of a typical particle in the sizerange. Mass of a typical particle in a given size range=π*D³*φ/6, whereD is a typical particle diameter in the size range (generally, the meanboundary MMADs defining the size range) in microns, 100 is the particledensity (in g/mL) and mass is given in units of picograms (g⁻¹²).

Rate of inhalable aerosol particle formation is determined, for example,by delivering aerosol phase drug into a confined chamber via aninhalation device. The delivery is for a set period of time (e.g., 3 s),and the number of particles of a given size collected in the chamber isdetermined as outlined above. The rate of particle formation is equal tothe number of 100 nm to 5 micron particles collected divided by theduration of the collection time.

Rate of aerosol formation is determined, for example, by deliveringaerosol phase drug into a confined chamber via an inhalation device. Thedelivery is for a set period of time (e.g., 3 s), and the mass ofparticulate matter collected is determined by weighing the confinedchamber before and after the delivery of the particulate matter. Therate of aerosol formation is equal to the increase in mass in thechamber divided by the duration of the collection time. Alternatively,where a change in mass of the delivery device or component thereof canonly occur through release of the aerosol phase particulate matter, themass of particulate matter may be equated with the mass lost from thedevice or component during the delivery of the aerosol. In this case,the rate of aerosol formation is equal to the decrease in mass of thedevice or component during the delivery event divided by the duration ofthe delivery event.

Rate of drug aerosol formation is determined, for example, by deliveringa sumatriptan, frovatriptan, or naratriptan containing aerosol into aconfined chamber via an inhalation device over a set period of time(e.g., 3 s). Where the aerosol is pure sumatriptan, frovatriptan, ornaratriptan, the amount of drug collected in the chamber is measured asdescribed above. The rate of drug aerosol formation is equal to theamount of sumatriptan, frovatriptan, or naratriptan collected in thechamber divided by the duration of the collection time. Where thesumatriptan, frovatriptan, or naratriptan containing aerosol comprises apharmaceutically acceptable excipient, multiplying the rate of aerosolformation by the percentage of sumatriptan, frovatriptan, or naratriptanin the aerosol provides the rate of drug aerosol formation.

Utility of Sumatriptan, Frovatriptan, or Naratriptan Containing Aerosols

The sumatriptan, frovatriptan, or naratriptan containing aerosols of thepresent invention are typically used for the treatment of migraineheadaches.

The following examples are meant to illustrate, rather than limit, thepresent invention.

Sumatriptan, frovatriptan and naratriptan are commercially available asthe active ingredients in tablets sold as IMITREX® (sumitriptan), FROVA®(frovatriptan succinate), and AMERGE® (naratriptan hydrochloride)respectively.

EXAMPLE 1 General Procedure for Obtaining Free Base of a Compound Salt

Approximately 1 g of salt (e.g., mono hydrochloride) is dissolved indeionized water (˜30 mL). Three equivalents of sodium hydroxide (1 NNaOH_(aq)) is added dropwise to the solution, and the pH is checked toensure it is basic. The aqueous solution is extracted four times withdichloromethane (˜50 mL), and the extracts are combined, dried (Na₂SO₄)and filtered. The filtered organic solution is concentrated using arotary evaporator to provide the desired free base. If necessary,purification of the free base is performed using standard methods suchas chromatography or recrystallization.

EXAMPLE 2 General Procedure for Volatilizing Compounds from Halogen Bulb

A solution of drug in approximately 120 μL dichloromethane is coated ona 3.5 cm×7.5 cm piece of aluminum foil (precleaned with acetone). Thedichloromethane is allowed to evaporate. The coated foil is wrappedaround a 300 watt halogen tube (Feit Electric Company, Pico Rivera,Calif.), which is inserted into a glass tube sealed at one end with arubber stopper. Running 118 V of alternating current (driven by linepower controlled by a variac) through the bulb for 2.2 s affords thermalvapor (including aerosol), which is collected on the glass tube walls.Reverse-phase HPLC analysis with detection by absorption of 225 nm lightis used to determine the purity of the aerosol. (When desired, thesystem is flushed through with argon prior to volatilization.)

The following aerosols were obtained using this procedure: sumatriptanaerosol (˜0.56 mg, 97.2% purity); frovatriptan aerosol (0.39 mg, 94.8%purity); and, naratriptan aerosol (0.58 mg, 96.2% purity). To obtainhigher purity aerosols, one can coat a lesser amount of drug, yielding athinner film to heat. A linear decrease in film thickness is associatedwith a linear decrease in impurities.

EXAMPLE 3 Particle Size, Particle Density, and Rate of InhalableParticle Formation of Frovatriptan Aerosol

A solution of 5.0 mg frovatriptan in 100 μL methanol was spread out in athin layer on the central portion of a 3.5 cm×7 cm sheet of aluminumfoil. The methanol was allowed to evaporate. Assuming a drug density ofabout 1 g/cc, the calculated thickness of the frovatriptan thin layer onthe 24.5 cm² aluminum solid support, after solvent evaporation, is about2.0 microns. The aluminum foil was wrapped around a 300 watt halogentube, which was inserted into a T-shaped glass tube. Both of theopenings of the tube were left open and the third opening was connectedto a 1 liter, 3-neck glass flask. The glass flask was further connectedto a large piston capable of drawing 1.1 liters of air through theflask. Alternating current was run through the halogen bulb byapplication of 90 V using a variac connected to 110 V line power. Within1 s, an aerosol appeared and was drawn into the 1 L flask by use of thepiston, with collection of the aerosol terminated after 6 s. The aerosolwas analyzed by connecting the 1 L flask to an eight-stage Andersennon-viable cascade impactor. Results are shown in table 1. MMAD of thecollected aerosol was 1.8 microns with a geometric standard deviation of2.1. Also shown in table 1 is the number of particles collected on thevarious stages of the cascade impactor, given by the mass collected onthe stage divided by the mass of a typical particle trapped on thatstage. The mass of a single particle of diameter D is given by thevolume of the particle, πD³/6, multiplied by the density of the drug(taken to be 1 g/cm³). The inhalable aerosol particle density is the sumof the numbers of particles collected on impactor stages 3 to 8 dividedby the collection volume of 1 L, giving an inhalable aerosol particledensity of 7.3×10⁵ particles/mL. The rate of inhalable aerosol particleformation is the sum of the numbers of particles collected on impactorstages 3 through 8 divided by the formation time of 6 s, giving a rateof inhalable aerosol particle formation of 1.2×10⁸ particles/second.

TABLE 1 Determination of the characteristics of a frovatriptancondensation aerosol by cascade impaction using an Andersen 8-stagenon-viable cascade impactor run at 1 cubic foot per minute air flow.Mass Particle size Average particle collected Number of Stage range(microns) size (microns) (mg) particles 0  9.0-10.0 9.5 0.01 1.3 × 10⁴ 15.8-9.0 7.4 0.02 8.0 × 10⁴ 2 4.7-5.8 5.25 0.03 3.8 × 10⁵ 3 3.3-4.7 4.00.05 1.6 × 10⁶ 4 2.1-3.3 2.7 0.09 9.1 × 10⁶ 5 1.1-2.1 1.6 0.16 7.6 × 10⁷6 0.7-1.1 0.9 0.09 2.4 × 10⁸ 7 0.4-0.7 0.55 0.04 4.0 × 10⁸ 8   0-0.4 0.20.0 0

EXAMPLE 4 Drug Mass Density and Rate of Drug Aerosol Formation ofFrovatriptan Aerosol

A solution of 5.0 mg frovatriptan in 100 μL methanol was spread out in athin layer on the central portion of a 3.5 cm×7 cm sheet of aluminumfoil. Assuming a drug density of about 1 g/cc, the calculated thicknessof the frovatriptan thin layer on the 24.5 cm² aluminum solid support,after solvent evaporation, is about 2.0 microns. The methanol wasallowed to evaporate. The aluminum foil was wrapped around a 300 watthalogen tube, which was inserted into a T-shaped glass tube. Both of theopenings of the tube were left open and the third opening was connectedto a 1 liter, 3-neck glass flask. The glass flask was further connectedto a large piston capable of drawing 1.1 liters of air through theflask. Alternating current was run through the halogen bulb byapplication of 90 V using a variac connected to 110 V line power. Withinseconds, an aerosol appeared and was drawn into the 1 L flask by use ofthe piston, with formation of the aerosol terminated after 6 s. Theaerosol was allowed to sediment onto the walls of the 1 L flask forapproximately 30 minutes. The flask was then extracted with acetonitrileand the extract analyzed by HPLC with detection by light absorption at225 nm. Comparison with standards containing known amounts offrovatriptan revealed that 0.85 mg of >91% pure frovatriptan had beencollected in the flask, resulting in an aerosol drug mass density of0.85 mg/L. The aluminum foil upon which the frovatriptan had previouslybeen coated was weighed following the experiment. Of the 5.0 mgoriginally coated on the aluminum, 2.8 mg of the material was found tohave aerosolized in the 6 s time period, implying a rate of drug aerosolformation of 0.5 mg/s.

EXAMPLE 5 Flash Device for Forming Aerosols

A high-power flashcube (GE or Sylvania), which can produce 300-400 J ofenergy, was inserted into an anodized aluminum tube. The flashcube/tubeassembly was dipped into an organic solution containing a drug andquickly removed. Evaporation of residual solvent from the assembly wasperformed by placing it into a vacuum chamber for 30 min. This left afilm of drug coated on the exterior surface of the aluminum tube. Theflashbulb assembly was electrically connected to two 1.5 V batteries anda switch using copper wires and then enclosed in a sealed, glass vial.Ignition of the flashbulb was performed by momentarily turning on theswitch between the flashbulb and batteries. After ignition, the vial waskept closed for 30 minutes such that particles of volatilized drugcoagulated and condensed on the inside surface of the vial. Analysis ofthe aerosol involved rinsing the vial with 5 mL of acetonitrile andinjecting a sample of the organic solution into an HPLC. Frovatriptan(0.45 mg) aerosol was obtained in approximately 92% purity using thisprocedure.

What is claimed is:
 1. A composition for delivery of sumatriptan, frovatriptan, or naratriptan comprising a condensation aerosol a) formed by volatilizing sumatriptan, frovatriptan, or naratriptan under conditions effective to produce a heated vapor of the sumatriptan, frovatriptan, or naratriptan and condensing the heated vapor of the sumatriptan, frovatriptan, or naratriptan to form condensation aerosol particles, b) wherein said condensation aerosol particles are characterized by less that 5% sumatriptan, frovatriptan, or naratriptan degradation products, and c) wherein the aerosol MMAD is less than 3 microns.
 2. The composition according to claim 1, wherein the condensation aerosol particles comprise at least 90 percent by weight of sumatriptan, frovatriptan, or naratriptan.
 3. The composition according to claim 2, wherein the condensation aerosol has a mass median aerodynamic diameter less than 2 microns.
 4. The aerosol according to claim 3, wherein the condensation aerosol particles comprise at least 95 percent by weight of sumatriptan, frovatriptan, or naratriptan.
 5. A method of producing sumatriptan, frovatriptan, or naratriptan in an aerosol form comprising: a) volatilizing sumatriptan, frovatriptan, or naratriptan under conditions effective to produce a heated vapor of sumatriptan, frovatriptan, or naratriptan, and b) during said volatilizing, passing air through the heated vapor to produce aerosol particles of sumatriptan, frovatriptan, or naratriptan comprising less than 5% sumatriptan, frovatriptan, or naratriptan degradation products and an aerosol having an MMAD less than 3 μm.
 6. The method according to claim 5, wherein the aerosol particles are formed at a rate of greater than 0.5 mg/sec.
 7. The method according to claim 5, wherein the said volatilizing includes heating a thin layer which includes the sumatriptan, frovatriptan, or naratriptan and which is on a solid support having the surface texture of a metal foil, to a temperature sufficient to volatilize the sumatriptan, frovatriptan, or naratriptan from the thin layer.
 8. The method according to claim 5, wherein the aerosol particles comprise at least 90 percent by weight of sumatriptan, frovatriptan, or naratriptan.
 9. The method according to claim 8, wherein the aerosol has a mass median aerodynamic diameter less than 2 microns.
 10. The method according to claim 9, wherein the aerosol particles comprise at least 95 percent by weight of sumatriptan or naratriptan. 